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Current Research for Heart Disease Biology and Therapeutics

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (28 February 2024) | Viewed by 11662

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Special Issue Editor

Dr. Claudia Kusmic

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Guest Editor

Insitute of Clinical Physiology, National Research Council (IFC-CNR), 56124 Pisa, Italy
Interests: preclinical models; in vivo models of cardiac hypertrophy and cardiotoxicity; cardiovascular disease; obesity; mitochondrial damage; cardio-oncology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

“Heart disease” refers to several types of heart conditions. For example, Pathological cardiac hypertrophy is a key risk factor for heart failure. Increased interstitial fibrosis, cardiac dysfunction and cell death are essential features of pathological cardiac hypertrophy. The numerous mediators that have been found as involved in the pathogenesis of maladaptive heart growth can affect gene transcription, calcium handling, protein synthesis, metabolism, mitochondrial function, autophagy, oxidative stress and inflammation. Many of the molecular mechanisms and dysregulated signaling pathways implicated in promoting malignant remodeling have been unrevealed. Focusing on these key regulation points seems to be an important target for defining innovative strategies for the management of heart disease.

This special issue aims to take stock of advances in the development and validation of therapeutic strategies against heart disease, Research papers and up-to-date review articles are all welcome on various topics including, but not limited to, either conventional drug strategies or novel therapeutic approaches (e.g., RNA-based therapies, dietary supplementation, drug delivery systems) targeting molecular pathways involved in the transition to heart disease biology and therapeutics.

Dr. Claudia Kusmic
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

myocardial hypertrophy
cardiac remodeling
heart failure
drug therapy
molecular therapeutic targets
myocardial gene therapy
heart disease

Published Papers (10 papers)

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Research

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17 pages, 3384 KiB

Open AccessArticle

Early Impairment of Paracrine and Phenotypic Features in Resident Cardiac Mesenchymal Stromal Cells after Thoracic Radiotherapy

by Vittorio Picchio, Roberto Gaetani, Francesca Pagano, Yuriy Derevyanchuk, Olivia Pagliarosi, Erica Floris, Claudia Cozzolino, Giacomo Bernava, Antonella Bordin, Filipe Rocha, Ana Rita Simões Pereira, Augusto Ministro, Ana Teresa Pinto, Elena De Falco, Gianpaolo Serino, Diana Massai, Radia Tamarat, Maurizio Pesce, Susana Constantino Rosa Santos, Elisa Messina and Isotta Chimenti Show full author list Hide full author list

Int. J. Mol. Sci. 2024, 25(5), 2873; https://doi.org/10.3390/ijms25052873 - 01 Mar 2024

Viewed by 1017

Abstract

Radiotherapy-induced cardiac toxicity and consequent diseases still represent potential severe late complications for many cancer survivors who undergo therapeutic thoracic irradiation. We aimed to assess the phenotypic and paracrine features of resident cardiac mesenchymal stromal cells (CMSCs) at early follow-up after the end of thoracic irradiation of the heart as an early sign and/or mechanism of cardiac toxicity anticipating late organ dysfunction. Resident CMSCs were isolated from a rat model of fractionated thoracic irradiation with accurate and clinically relevant heart dosimetry that developed delayed dose-dependent cardiac dysfunction after 1 year. Cells were isolated 6 and 12 weeks after the end of radiotherapy and fully characterized at the transcriptional, paracrine, and functional levels. CMSCs displayed several altered features in a dose- and time-dependent trend, with the most impaired characteristics observed in those exposed in situ to the highest radiation dose with time. In particular, altered features included impaired cell migration and 3D growth and a and significant association of transcriptomic data with GO terms related to altered cytokine and growth factor signaling. Indeed, the altered paracrine profile of CMSCs derived from the group at the highest dose at the 12-week follow-up gave significantly reduced angiogenic support to endothelial cells and polarized macrophages toward a pro-inflammatory profile. Data collected in a clinically relevant rat model of heart irradiation simulating thoracic radiotherapy suggest that early paracrine and transcriptional alterations of the cardiac stroma may represent a dose- and time-dependent biological substrate for the delayed cardiac dysfunction phenotype observed in vivo. Full article

(This article belongs to the Special Issue Current Research for Heart Disease Biology and Therapeutics)

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17 pages, 2906 KiB

Open AccessArticle

Anserine, a Histidine-Containing Dipeptide, Suppresses Pressure Overload-Induced Systolic Dysfunction by Inhibiting Histone Acetyltransferase Activity of p300 in Mice

by Yoichi Sunagawa, Ryosuke Tsukabe, Yudai Irokawa, Masafumi Funamoto, Yuto Suzuki, Miho Yamada, Satoshi Shimizu, Yasufumi Katanasaka, Toshihide Hamabe-Horiike, Yuto Kawase, Ryuya Naruta, Kana Shimizu, Kiyoshi Mori, Ryota Hosomi, Maki Komiyama, Koji Hasegawa and Tatsuya Morimoto

Int. J. Mol. Sci. 2024, 25(4), 2344; https://doi.org/10.3390/ijms25042344 - 16 Feb 2024

Viewed by 752

Abstract

Anserine, an imidazole dipeptide, is present in the muscles of birds and fish and has various bioactivities, such as anti-inflammatory and anti-fatigue effects. However, the effect of anserine on the development of heart failure remains unknown. We cultured primary cardiomyocytes with 0.03 mM to 10 mM anserine and stimulated them with phenylephrine for 48 h. Anserine significantly suppressed the phenylephrine-induced increases in cardiomyocyte hypertrophy, ANF and BNP mRNA levels, and histone H3K9 acetylation. An in vitro histone acetyltransferase (HAT) assay showed that anserine directly suppressed p300-HAT activity with an IC₅₀ of 1.87 mM. Subsequently, 8-week-old male C57BL/6J mice were subjected to transverse aortic constriction (TAC) and were randomly assigned to receive daily oral treatment with anserine-containing material, Marine Active^® (60 or 200 mg/kg anserine) or vehicle for 8 weeks. Echocardiography revealed that anserine 200 mg/kg significantly prevented the TAC-induced increase in left ventricular posterior wall thickness and the decrease in left ventricular fractional shortening. Moreover, anserine significantly suppressed the TAC-induced acetylation of histone H3K9. These results indicate that anserine suppresses TAC-induced systolic dysfunction, at least in part, by inhibiting p300-HAT activity. Anserine may be used as a pharmacological agent for human heart failure therapy. Full article

(This article belongs to the Special Issue Current Research for Heart Disease Biology and Therapeutics)

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15 pages, 4020 KiB

Open AccessArticle

Lithium Treatment Induces Cardiac Dysfunction in Mice

by Serena L’Abbate, Giuseppina Nicolini, Sabrina Marchetti, Gianpiero Forte, Elisa Lepore, Virginia Unfer and Claudia Kusmic

Int. J. Mol. Sci. 2023, 24(21), 15872; https://doi.org/10.3390/ijms242115872 - 01 Nov 2023

Cited by 1 | Viewed by 999

Abstract

Lithium (Li) salts are commonly used as medications for bipolar disorders. In addition to its therapeutic value, Li is also being increasingly used as a battery component in modern electronic devices. Concerns about its toxicity and negative impact on the heart have recently been raised. We investigated the effects of long-term Li treatment on the heart, liver, and kidney in mice. Sixteen C57BL/6J mice were randomly assigned to receive oral administration of Li carbonate (n = 8) or act as a control group (n = 8) for 12 weeks. We evaluated the cardiac electrical activity, morphology and function, and pathways contributing to remodelling. We assessed the multi-organ toxicity using histopathology techniques in the heart, liver, and kidney. Our findings suggest that mice receiving Li had impaired systolic function and ventricular repolarisation and were more susceptible to arrhythmias under adrenergic stimulation. The Li treatment caused an increase in the cardiomyocytes’ size, the modulation of the extracellular signal-regulated kinase (ERK) pathway, along with some minor tissue damage. Our findings revealed a cardiotoxic effect of Li at therapeutic dosage, along with some histopathological alterations in the liver and kidney. In addition, our study suggests that our model could be used to test potential treatments for Li-induced cardiotoxicity. Full article

(This article belongs to the Special Issue Current Research for Heart Disease Biology and Therapeutics)

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13 pages, 2738 KiB

Open AccessArticle

Plasma miR-486-5p Expression Is Upregulated in Atrial Fibrillation Patients with Broader Low-Voltage Areas

by María Cebro-Márquez, Moisés Rodríguez-Mañero, Valentina Serrano-Cruz, Marta E. Vilar-Sánchez, Laila González-Melchor, Javier García-Seara, José Luis Martínez-Sande, Alana Aragón-Herrera, María Amparo Martínez-Monzonís, José Ramón González-Juanatey, Ricardo Lage and Isabel Moscoso

Int. J. Mol. Sci. 2023, 24(20), 15248; https://doi.org/10.3390/ijms242015248 - 17 Oct 2023

Viewed by 933

Abstract

Atrial fibrillation (AF) is the most common arrhythmia worldwide, affecting 1% of the population over 60 years old. The incidence and prevalence of AF are increasing globally, representing a relevant health problem, suggesting that more advanced strategies for predicting risk stage are highly needed. miRNAs mediate several processes involved in AF. Our aim was to identify miRNAs with a prognostic value as biomarkers in patients referred for AF ablation and its association with LVA extent, based on low-voltage area (LVA) maps. In this study, we recruited 44 AF patients referred for catheter ablation. We measured the expression of 84 miRNAs in plasma from peripheral blood in 3 different groups based on LVA extent. Expression analysis showed that miR-486-5p was significantly increased in patients with broader LVA (4-fold, p = 0.0002; 5-fold, p = 0.0001). Receiver operating characteristic curve analysis showed that miR-486-5p expression could predict atrium LVA (AUC, 0.8958; p = 0.0015). Also, miR-486-5p plasma levels were associated with AF-type (AUC, 0.7137; p = 0.0453). In addition, miR-486-5p expression was positively correlated with LVA percentage, left atrial (LA) area, and LA volume (r = 0.322, p = 0.037; r = 0.372, p = 0.015; r = 0.319, p = 0.045, respectively). These findings suggest that miR-486-5p expression might have prognostic significance in LVA extent in patients with AF. Full article

(This article belongs to the Special Issue Current Research for Heart Disease Biology and Therapeutics)

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Review

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20 pages, 1566 KiB

Open AccessReview

Synergistic Effects of Weight Loss and Catheter Ablation: Can microRNAs Serve as Predictive Biomarkers for the Prevention of Atrial Fibrillation Recurrence?

by Carola Y. Förster, Stephan R. Künzel, Sergey Shityakov and Stavros Stavrakis

Int. J. Mol. Sci. 2024, 25(9), 4689; https://doi.org/10.3390/ijms25094689 - 25 Apr 2024

Viewed by 222

Abstract

In atrial fibrillation (AF), multifactorial pathologic atrial alterations are manifested by structural and electrophysiological changes known as atrial remodeling. AF frequently develops in the context of underlying cardiac abnormalities. A critical mechanistic role played by atrial stretch is played by abnormal substrates in a number of conditions that predispose to AF, including obesity, heart failure, hypertension, and sleep apnea. The significant role of overweight and obesity in the development of AF is known; however, the differential effect of overweight, obesity, cardiovascular comorbidities, lifestyle, and other modifiable risk factors on the occurrence and recurrence of AF remains to be determined. Reverse remodeling of the atrial substrate and subsequent reduction in the AF burden by conversion into a typical sinus rhythm has been associated with weight loss through lifestyle changes or surgery. This makes it an essential pillar in the management of AF in obese patients. According to recently published research, microRNAs (miRs) may function as post-transcriptional regulators of genes involved in atrial remodeling, potentially contributing to the pathophysiology of AF. The focus of this review is on their modulation by both weight loss and catheter ablation interventions to counteract atrial remodeling in AF. Our analysis outlines the experimental and clinical evidence supporting the synergistic effects of weight loss and catheter ablation (CA) in reversing atrial electrical and structural remodeling in AF onset and in recurrent post-ablation AF by attenuating pro-thrombotic, pro-inflammatory, pro-fibrotic, arrhythmogenic, and male-sex-associated hypertrophic remodeling pathways. Furthermore, we discuss the promising role of miRs with prognostic potential as predictive biomarkers in guiding approaches to AF recurrence prevention. Full article

(This article belongs to the Special Issue Current Research for Heart Disease Biology and Therapeutics)

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19 pages, 2840 KiB

Open AccessReview

Vitamin C as Scavenger of Reactive Oxygen Species during Healing after Myocardial Infarction

by Huabo Zheng, Yichen Xu, Elisa A. Liehn and Mihaela Rusu

Int. J. Mol. Sci. 2024, 25(6), 3114; https://doi.org/10.3390/ijms25063114 - 07 Mar 2024

Viewed by 1011

Abstract

Currently, coronary artery bypass and reperfusion therapies are considered the gold standard in long-term treatments to restore heart function after acute myocardial infarction. As a drawback of these restoring strategies, reperfusion after an ischemic insult and sudden oxygen exposure lead to the exacerbated synthesis of additional reactive oxidative species and the persistence of increased oxidation levels. Attempts based on antioxidant treatment have failed to achieve an effective therapy for cardiovascular disease patients. The controversial use of vitamin C as an antioxidant in clinical practice is comprehensively systematized and discussed in this review. The dose-dependent adsorption and release kinetics mechanism of vitamin C is complex; however, this review may provide a holistic perspective on its potential as a preventive supplement and/or for combined precise and targeted therapeutics in cardiovascular management therapy. Full article

(This article belongs to the Special Issue Current Research for Heart Disease Biology and Therapeutics)

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13 pages, 1039 KiB

Open AccessReview

Role of the Alpha-B-Crystallin Protein in Cardiomyopathic Disease

by Andres Thorkelsson and Michael T. Chin

Int. J. Mol. Sci. 2024, 25(5), 2826; https://doi.org/10.3390/ijms25052826 - 29 Feb 2024

Viewed by 762

Abstract

Alpha-B-crystallin, a member of the small heat shock family of proteins, has been implicated in a variety of cardiomyopathies and in normal cardiac homeostasis. It is known to function as a molecular chaperone, particularly for desmin, but also interacts with a wide variety of additional proteins. The molecular chaperone function is also enhanced by signal-dependent phosphorylation at specific residues under stress conditions. Naturally occurring mutations in CRYAB, the gene that encodes alpha-B-crystallin, have been suggested to alter ionic intermolecular interactions that affect dimerization and chaperone function. These mutations have been associated with myofibrillar myopathy, restrictive cardiomyopathy, and hypertrophic cardiomyopathy and promote pathological hypertrophy through different mechanisms such as desmin aggregation, increased reductive stress, or activation of calcineurin–NFAT signaling. This review will discuss the known mechanisms by which alpha-B-crystallin functions in cardiac homeostasis and the pathogenesis of cardiomyopathies and provide insight into potential future areas of exploration. Full article

(This article belongs to the Special Issue Current Research for Heart Disease Biology and Therapeutics)

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36 pages, 594 KiB

Open AccessReview

The Role of Pro-Inflammatory Cytokines in the Pathogenesis of Cardiovascular Disease

by Hannah Zhang and Naranjan S. Dhalla

Int. J. Mol. Sci. 2024, 25(2), 1082; https://doi.org/10.3390/ijms25021082 - 16 Jan 2024

Cited by 3 | Viewed by 2581

Abstract

With cardiovascular disease (CVD) being a primary source of global morbidity and mortality, it is crucial that we understand the molecular pathophysiological mechanisms at play. Recently, numerous pro-inflammatory cytokines have been linked to several different CVDs, which are now often considered an adversely pro-inflammatory state. These cytokines most notably include interleukin-6 (IL-6),tumor necrosis factor (TNF)α, and the interleukin-1 (IL-1) family, amongst others. Not only does inflammation have intricate and complex interactions with pathophysiological processes such as oxidative stress and calcium mishandling, but it also plays a role in the balance between tissue repair and destruction. In this regard, pre-clinical and clinical evidence has clearly demonstrated the involvement and dynamic nature of pro-inflammatory cytokines in many heart conditions; however, the clinical utility of the findings so far remains unclear. Whether these cytokines can serve as markers or risk predictors of disease states or act as potential therapeutic targets, further extensive research is needed to fully understand the complex network of interactions that these molecules encompass in the context of heart disease. This review will highlight the significant advances in our understanding of the contributions of pro-inflammatory cytokines in CVDs, including ischemic heart disease (atherosclerosis, thrombosis, acute myocardial infarction, and ischemia-reperfusion injury), cardiac remodeling (hypertension, cardiac hypertrophy, cardiac fibrosis, cardiac apoptosis, and heart failure), different cardiomyopathies as well as ventricular arrhythmias and atrial fibrillation. In addition, this article is focused on discussing the shortcomings in both pathological and therapeutic aspects of pro-inflammatory cytokines in CVD that still need to be addressed by future studies. Full article

(This article belongs to the Special Issue Current Research for Heart Disease Biology and Therapeutics)

14 pages, 2147 KiB

Open AccessReview

Off-Target Effects of P2Y12 Receptor Inhibitors: Focus on Early Myocardial Fibrosis Modulation

by Francesca Lofrumento, Natasha Irrera, Roberto Licordari, Silvia Perfetti, Enrica Nasso, Paolo Liotta, Giovanni Isgrò, Victoria Garcia-Ruiz, Francesco Squadrito, Scipione Carerj, Gianluca Di Bella, Antonio Micari and Francesco Costa

Int. J. Mol. Sci. 2023, 24(24), 17546; https://doi.org/10.3390/ijms242417546 - 16 Dec 2023

Cited by 1 | Viewed by 1232

Abstract

Several studies have demonstrated that, beyond their antithrombotic effects, P2Y12 receptor inhibitors may provide additional off-target effects through different mechanisms. These effects range from the preservation of endothelial barrier function to the modulation of inflammation or stabilization of atherosclerotic plaques, with an impact on different cell types, including endothelial and immune cells. Many P2Y12 inhibitors have been developed, from ticlopidine, the first thienopyridine, to the more potent non-thienopyridine derivatives such as ticagrelor which may promote cardioprotective effects following myocardial infarction (MI) by inhibiting adenosine reuptake through sodium-independent equilibrative nucleoside transporter 1 (ENT1). Adenosine may affect different molecular pathways involved in cardiac fibrosis, such as the Wnt (wingless-type)/beta (β)-catenin signaling. An early pro-fibrotic response of the epicardium and activation of cardiac fibroblasts with the involvement of Wnt1 (wingless-type family member 1)/β-catenin, are critically required for preserving cardiac function after acute ischemic cardiac injury. This review discusses molecular signaling pathways involved in cardiac fibrosis post MI, focusing on the Wnt/β-catenin pathway, and the off-target effect of P2Y12 receptor inhibition. A potential role of ticagrelor was speculated in the early modulation of cardiac fibrosis, thanks to its off-target effect. Full article

(This article belongs to the Special Issue Current Research for Heart Disease Biology and Therapeutics)

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29 pages, 4609 KiB

Open AccessReview

miRNAs Epigenetic Tuning of Wall Remodeling in the Early Phase after Myocardial Infarction: A Novel Epidrug Approach

by Francesca Salvatori, Elisabetta D’Aversa, Maria Luisa Serino, Ajay Vikram Singh, Paola Secchiero, Giorgio Zauli, Veronica Tisato and Donato Gemmati

Int. J. Mol. Sci. 2023, 24(17), 13268; https://doi.org/10.3390/ijms241713268 - 26 Aug 2023

Cited by 4 | Viewed by 1108

Abstract

Myocardial infarction (MI) is one of the leading causes of death in Western countries. An early diagnosis decreases subsequent severe complications such as wall remodeling or heart failure and improves treatments and interventions. Novel therapeutic targets have been recognized and, together with the development of direct and indirect epidrugs, the role of non-coding RNAs (ncRNAs) yields great expectancy. ncRNAs are a group of RNAs not translated into a product and, among them, microRNAs (miRNAs) are the most investigated subgroup since they are involved in several pathological processes related to MI and post-MI phases such as inflammation, apoptosis, angiogenesis, and fibrosis. These processes and pathways are finely tuned by miRNAs via complex mechanisms. We are at the beginning of the investigation and the main paths are still underexplored. In this review, we provide a comprehensive discussion of the recent findings on epigenetic changes involved in the first phases after MI as well as on the role of the several miRNAs. We focused on miRNAs function and on their relationship with key molecules and cells involved in healing processes after an ischemic accident, while also giving insight into the discrepancy between males and females in the prognosis of cardiovascular diseases. Full article

(This article belongs to the Special Issue Current Research for Heart Disease Biology and Therapeutics)

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